PROJECT SUMMARY/ABSTRACT Candidate: Dr. Natalie Nokoff is a Pediatric Endocrinologist whose research and clinical focus is on the cardiometabolic health of transgender youth. The goal of her K23 proposal is to acquire the critical research skills necessary to lead high-quality, patient-centered clinical research. This training will help her achieve her long-term goal of developing a successful independent research program and becoming an international expert on the impact of sex steroids on cardiometabolic health. Background: Up to 1.8% of adolescents in the U.S. identify as transgender. Treatment of transgender females (male sex and a female gender identity, MTF) may include pubertal blockade (gonadotropin-releasing hormone analogue or GnRHa) in early puberty followed by estradiol later in adolescence. The impact of these treatments on cardiometabolic health is understudied and unclear. MTF adults on estradiol have higher rates of vascular events than non-transgender (cisgender) individuals. Research Plan: Pubertal Blockade and Estradiol Effects on Cardiometabolic Health for Transitioning Youth (PUBERTY) is a longitudinal observational study to evaluate the impact of GnRHa and estradiol on vascular function and insulin sensitivity (IS). Young MTF (n=15) will be evaluated before and 6 months after GnRHa. A separate cohort of MTF youth (n=40, ages 13-16 years, 20 who clinically received a GnRHa and 20 who did not) will be evaluated at baseline, 6 and 12 months after estradiol. MTF youth will be compared to cisgender youth (n=15 males, 15 females), adjusted to pubertal stage and body mass. Career Development Plan: Dr. Nokoff?s research career development training activities include: 1) gain expertise in design and conduct of clinical studies (implementation and completion of the PUBERTY study, coursework and a PhD in Clinical Investigation); 2) lean how to perform and interpret vascular studies; 3) learn new methods for assessing IS. Environment: The environment for this project is exceptional with a strong academic Section of Pediatric Endocrinology at the University of Colorado Anschutz Medical Campus and resources of the Colorado Clinical and Translational Sciences Institute and Center for Women?s Health Research. Dr. Nokoff is faculty in the TRUE Center for Gender Diversity, a comprehensive, multidisciplinary clinic serving over 1,000 transgender youth, that will assure successful recruitment for this study. Mentors with expertise in endocrinology, insulin resistance, vascular health, sex steroids, working with vulnerable populations, and clinical investigation are invested in this candidate?s future and will be instrumental in supporting her research and career development. Impact: The results of this novel study will improve the clinical care of transgender youth and yield information on risk factors for future vascular events. Dr. Nokoff will gain invaluable skills in study design as well as assessment of vascular and metabolic health, launching an impactful career as a lead clinical investigator.